Clear vision requires the ability to coordinate the movements of the eyes and head to control gaze, which is where we look in space. This project is devoted to understanding the nature of neuronal and muscular mechanisms underlying the neural control of gaze. This project constructs and tests mathematical models of sensory and motor functions involved in the control of gaze, based on experimentally observed neuronal activity during normal behavior, and deficits that arise in clinical eye movement disorders. Neural Control of Movement Current work in our laboratory is using functionally realistic models of circuits in the cerebellum, midbrain and brain stem to evaluate the mechanism underlying gaze control. Additionally, this theoretical approach is also being extended to the study of vergence eye movements. Vergence movements are the disconjugate movements made when the eyes look at objects at different distances. Closer objects require convergence of the two eyes, and farther objects require divergence of the eyes. Importantly, failures of the vergence mechanism may be related to the inappropriate ocular alignment seen in infantile strabismus (esotropias result from too much convergence, and exotropias result from too much divergence). Surprisingly, how the brain maintains the alignment of the two eyes is still unknown. A theoretical study may elucidate much of the existing clinical data on strabismus and its surgical treatment, and may suggest improved methods for characterizing and treating strabismus. Eye Head Coordination Gaze saccades (coordinated eye and head movements) could be controlled by a single gaze controller, with eye and head movements sharing a common motor drive. However, experimental evidence has shown that eye and head trajectories can be decoupled by changes in initial eye and head position. This evidence has led to gaze models based on independent eye and head controllers. However, they cannot determine the end of the gaze shift if the onset and speed of the head movement vary. We propose a model of gaze saccades based on two separate controllers, one for gaze and one for head, but no separate controller for eye. This model extends that of Lefevre et al. (1998) by introducing a duplicate structure in the cerebellum (CB) for controlling the head. The core of the model is a CB controller that monitors movement progress by integrating velocity feedback signals. Eye velocity feedback comes from an efference copy of the eye motor command, and head velocity feedback comes from semicircular canal afference. Gaze velocity (the sum of eye and head velocity) feeds back to the gaze-CB. Head velocity feeds back to the head-CB. The gaze-CB drives the eye and the head-CB drives the head. These drives complement the common gaze drive signal, shared by eye and head, which comes from the superior colliculus (SC). The SC and the gaze-CB receive an input related to the desired change in gaze. The head-CB receives a desired change in head position signal that depends on movement context. During a gaze shift, the VOR is turned off and the gaze-CB provides a drive compensating for the variability in the head trajectory. When gaze reaches the target, the VOR is restored and stabilizes gaze despite any remaining head movement. Although the head contributes to gaze in this model, the head can have an independent goal, because any variability in its trajectory is treated as a perturbation by the gaze controller. Clincal Eye Movement Disorders We have also looked at several clinical eye movement disorders. Several have to do with oscillations caused by aberrant firing of powerful premotor burst neurons in the brain stem. Our recent models of brain stem neurons include the biophysical properties of voltage- and ligand-dependent ion channels. This has enabled us to models many eye movement disorders showing flutter. Another disorder is oculopalatal tremor (OPT). The etiology of OPT is unknown, and few treatments are successful. We have proposed a new model of hypertrophy of the inferior olive accompanied by learning in the cerebellum that reproduces most of the symptoms of OPT. It has also allowed us to recommend novel treatments to ameliorate its visual symptoms. Several patients are already being successfully treated with medications suggested by the model. Extraocular Muscles A major concern of the NM section is to understand how the brain moves the two eyes together. Failure of this coordination can result in misalignment of the eyes, called strabismus. Strabismus occurs in about 2-6% of the population, with about half of cases occurring in childhood. Strabismus is commonly treated surgically. Over a million strabismus surgeries are performed each year in the USA, and about the same number in the EU. Surgery has a poor success rate, depending upon the complexity of the type of strabismus, ranging from 50-80%. However, diagnosis of strabismus is difficult because of the limitations of common clinical tests, and surgical planning is limited to primitive recipe books and tables. The goal of this project is to provide improved diagnostic and surgical planning services to strabismus surgeons, with the hope of improving the success rate of surgery and thus reducing the number of re-operations. That will require major progress on two subprojects, modeling the orbit and the brain. We are advancing our understanding of the tissues in the orbit that make eye movements. Mechanical ophthalmotropes have been used since the 19th century to teach strabismus surgeons about the complex interactions of the twelve extraocular muscles. These were superseded in the late 20th century by computerized ophthalmotropes. However, these models could only account for the static properties of the orbit. There are currently four main static computer ophthalmotropes in development (by groups in California, England, The Netherlands, and Austria). All four of these models are based on one developed in 1975 by D.A. Robinson and J.M. Miller. The original work was severely hampered by a lack of anatomical and physiological data, which led to many unrealistic compromises. Many of these deficiencies persist in those models today. In 2003 we developed the first independent model of the human orbit. This was the first dynamic model of the orbit, and has now been extended to include the first sarcomere-based model of extraocular muscle dynamics, and the first model of co-contraction. The new model is being tested on data from clinical treatment of strabismus, and on data from monkeys with experimental fourth cranial nerve palsies. It has already uncovered some serious problems with earlier models, and shown the need for specific experimental data. This new model will provide a more physiological basis for understanding strabismus that should significantly improve the accuracy of clinical diagnoses and treatment planning. We are also attempting to join together the anatomical, neurophysiological, neurochemical, biophysical and genetic data about how the brain moves the eyes. This project has already had many breakthroughs, and it is hoped that coupling it to our advanced dynamic model of the orbit will provide a better understanding of the etiology and treatment of strabismus. The model is also being generalized to include neural control of head movement, to account for control of gaze (eye in space), the real-world function of the brain. Recently, we discovered that the viscoelastic properties of extraocular muscles (EOMs) in vivo differ from those previously assumed. We found that muscle force does not obey superposition during double step or double saccade tasks. This is an extremely important finding, because the way the muscle responds to multiple movements is critical to understanding how the eye moves in natural situations.